Review of cough and cold medicines in children

[Pages:27]Review of cough and cold medicines in children

21 April 2009

Review of cough and cold medicines in children

Contents

1. Terms of Reference ....................................................................................................3

2. Conflict of interest and disclaimer ............................................................................4

3. Setting the scene ........................................................................................................4

4. Current product availability and label claims ..........................................................5

5. `Coughs and colds' ? what are we treating? ............................................................7

6. Who uses these medicines? What do they expect from them? .............................8

7. Sedation: side-effect or desired effect? ...................................................................9

8. The need for better drugs ........................................................................................10

9. Epidemiology of childhood poisoning....................................................................10

10. Cough and cold medicines: Australia compared with US.................................12

11. TGA, cough and cold medicines and the general public...................................13

12. Dosage considerations.........................................................................................13

13. Review of the evidence.........................................................................................14

13.1 Antitussives for acute cough in children ........................................................................................ 14 13.1.1 Dextromethorphan ............................................................................................................................... 14 13.1.2 Codeine ................................................................................................................................................ 15 13.1.3 Pholcodine ........................................................................................................................................... 16 13.1.4 Dihydrocodeine.................................................................................................................................... 16

13.2 Expectorants for acute cough in children....................................................................................... 16 13.3 Antihistamine monotherapy for the common cold and acute cough in children............................ 17 13.4 Antihistamine-decongestant combinations for the common cold and acute cough in children ..... 19 13.5 Nasal decongestants for the common cold..................................................................................... 19

14. Summary and Discussion ....................................................................................21

14.1 General Considerations .................................................................................................................. 21 14.2 Efficacy: ......................................................................................................................................... 21 14.3 Safety: ............................................................................................................................................ 22

15. Possible courses of action: .................................................................................23

15.1 Maintain the `status quo'................................................................................................................ 23 15.2 Take rigid action based strictly on evidence: ................................................................................. 24 15.3 Take a more evolutionary approach ............................................................................................... 24

Table 1 Details of relevant and well-conducted controlled trials of antitussives, antihistamines and decongestants for acute cough. ...................................................26

Table 2: Relevant studies of antihistamines and antihistamine-decongestant combinations for the treatment of the common cold. ..................................................27

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1. Terms of Reference

The Contractor was requested to review the safety and efficacy of cough and cold medicines currently available in Australia for children aged less than 12 years, using journal articles, documents and other data supplied by the TGA and by sponsors. The report was also required to incorporate all information, facts, issues and opinions that the Contractor considered important and relevant. The TGA determined not to include, in the review, the large number of complementary medicines listed on the Australian Therapeutic Goods Register (ARTG) and marketed in Australia for the symptomatic relief of cough, cold or influenza.

The contractor interprets efficacy to relate to effectiveness of relief of cough and other symptoms of the common cold, in accord with the label claims of cough and cold medicines sold for use in children. The contractor interprets safety to include adverse effects of the medicines, either single drugs or a combination of drugs, of any severity, i.e. from minor, to death, in recommended dosages, but including also in non-intentional overdose where this is common.

The search strategy agreed to with the TGA was broad, because of the overlap of the use of drugs for coughs and colds and other conditions. This was to obviate as far as possible missing important references. However, the TGA and the reviewers agreed the report was not intended to extend to the safety and efficacy of cough and cold medicines for complications of colds, such as otitis media, otitis media with effusion and pneumonia.

The drug categories and individual drugs which are generally included in cough and cold medicines, and were therefore included in the TGA's search terms included ?

Antihistamines: brompheniramine maleate, chlorpheniramine maleate,

dexchlorpheniramine maleate, diphenhydramine hydro-

chloride, doxylamine succinate, pheniramine maleate,

promethazine hydrochloride, triprolidine hydrochloride

Antitussives: codeine phosphate, dextromethorphan hydrobromide,

dihydrocodeine tartrate, pentoxyverine citrate, pholcodine

Mucolytics: ammonium chloride, bromhexine hydrochloride, guaifenesin,

(guaiphenesin), ipecacuanha

Decongestants: phenylephrine hydrochloride, pseudoephedrine hydrochloride,

oxymetazoline hydrochloride, xylometazoline hydrochloride

The TGA conducted searches in Medline and Embase via the Ovid platform and for all available dates as well as information in the worldwide web using Google and Google scholar.

? The basic Ovid search strategy used was as follows: {ingredient} and (cough and cold or flu or influenza or antitussive or antihistamine or decongestant or expectorant) and (efficacy or effectiveness or safe or safety or adverse or hazard or warning or mortality or death or toxic or toxicity or toxicology or poison or poisoning or masking or mask or clinical trial or clinical trials).

? Google and Google scholar searches used appropriate combinations of the search key words: {ingredient name or therapeutic class} and (cough or cold or common cold or rhinitis) and (efficacy or effectiveness or clinical trial or safety).

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In addition the reviewers examined additional references obtained from other sources including those in industry submissions. Note that, in the report below, the terms `contractor' and `reviewers' are used interchangeably. This is because the TGA required there to be only one contractor, requiring the second reviewer to subcontract to the contractor.

2. Conflict of interest and disclaimer

The reviewers declare that neither (the contractor, nor his subcontractor) have any conflict of interest in regard to this report.

The reviewers have carried out this review as objectively as possible. Wherever possible, conclusions are based on evidence, but strong evidence is often not available on the subject of the review. The reviewers believe that evidence-based statements are recognizable as such in the report, as are any statements that are reflective, controversial and/or speculative. The latter have been provided in accordance with the terms of reference, with the intention of providing a comprehensive and useful background to assist the expert committee which will use the report in further advising the TGA.

3. Setting the scene

Almost all cough and cold medicines are S2 (pharmacy medicines). Almost all used in Australia are now, or soon will be, labelled as `not for use' in children less than 2 years of age. From early 2008, all sedating antihistamines have been categorized as `prescription only' in this age group. Nevertheless, the market overall for these drugs is very large, with many products for children aged less than 12 years.

Most cough and cold medicines contain combinations of drugs or sometimes a single drug and have been in use for at least 40 years. Indications for the uses of these drugs were accepted at much lower levels of evidence than would now be required, and there is no comprehensive review system for `grandfathered' uses of drugs. Use in children has usually been extrapolated from adult practice with no specific studies in children at all. The same has applied to doses used in children. The best that can be said is that there has been ample time for post marketing surveillance, and the adverse effects of drugs used in cough and cold medicines are generally well known, both in normal use and over-dosage.

There has been a background level of disquiet over the use of cough and cold medicines in children for many years. Paediatric specialists and academics have long pointed to the lack of evidence of benefit, and advised against use of these drugs. Concern has been expressed over side effects of drugs and drug combinations used in these medicines, both in `label' doses and in over-dose. A number of controlled trials have been undertaken in the past two decades and more recently three key Cochrane reviews of these agents for symptoms of the common cold have been published.1-3

Comprehensive review by the TGA of cough and cold medicines for use in children appears to have been prompted in part by a recent United States (US) Food and Drug Authority (FDA) review following a citizen petition seeking restriction of a wide range of over-the-counter (OTC) drugs for use in children, including but going beyond cough and cold medicines. Related to this, a multinational drug company application led to reconsideration of the scheduling of sedating antihistamines for use in children aged less than two years by the National Drugs and Poisons Schedule Committee (NDPSC).

A comment by an experienced poisons centre pharmacist being interviewed for a medical magazine highlights one aspect of the use of these drugs. `These drugs do bugger all', she said, `but people want something to give'. Natural concerns of parents for their sick children and for their own comfort are major factors in the use of drugs in common, discomforting illnesses of childhood. Even if currently available cough and cold medicines have little or no additional benefit over placebos, their extensive use indicates a perceived need for them within the community. This is no

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doubt part of a common public attitude of wanting a chemical remedy for every symptom, combined with active and sometimes entrepreneurial research and marketing of the drug manufacture and sales industry. The enormous attraction of self-medication ? something you can do for yourself or other family members ? is reflected in the enormous annual public spending on overthe-counter pharmaceuticals as well as on alternative medicines.

This review prompts long-stated but unanswered questions. If cough is a normal response to acute respiratory infection, or other airway irritation, secretions, foreign body, etc., might not cough suppression be harmful? The common wisdom is that a non-productive cough such as with the common cold has no benefit and, therefore, attempts to relieve it are justifiable. The `pain model' is possibly analogous. It is generally accepted that pain usually has a useful function, as an indicator of a problem, but that it is acceptable to relieve pain while simultaneously looking for its cause. However, there do not appear to be readily available antitussive drugs for acute cough with few or no side-effects, and that there is a need for such antitussives where there is an overall net benefit to the sufferer.

The review also prompts questions about the responsibilities of regulatory authorities to Australians generally. How efficacious/effective does a drug or drug combination need to be before it can be labelled as, for instance, for the relief of cough and other symptoms of the common cold in children? If evidence shows only a minimal effect, or an effect only in adults, is such labelling fair and informative? Where a medicine is being used entirely for symptom relief, and does not change the final outcome of any illness, what level of frequent, mild, or rare, severe side-effects can be tolerated?

Both internationally and within Australia, there is a strong emerging viewpoint that drugs should not be used in children without study of efficacy, safety and pharmacokinetics done specifically in children of the age-groups likely to receive those drugs. Applied broadly, this would deprive children of many useful drugs currently used for children, as well as new drugs as they become available. In the current context, the lack of studies done in children is a constantly-recurring feature.

1. Taverner D, Latte J. Nasal decongestants for the common cold. Cochrane.Database.Syst.Rev. 2007;CD001953.

2. Sutter AI, Lemiengre M, Campbell H, Mackinnon HF. Antihistamines for the common cold. Cochrane.Database.Syst.Rev. 2003;CD001267.

3. Smith SM, Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane.Database.Syst.Rev. 2008;CD001831.

4. Current product availability and label claims

MIMS Volume 45 No 3 (June/July 2008) and MIMS on-line list over 130 products in the category expectorants, antitussives, mucolytics and decongestants. Doses for children aged less than 12 years are supplied on the labels of more than 70 of these medicines, which are mostly scheduled as S2 (pharmacy medicines). After recent changes, all sedating antihistamines are now S4 drugs when used in children aged less than two years.

Far more drugs and drug combinations are used in cough and cold medicines in other countries, and this increases the difficulty in interpreting the literature on the subject, especially side effects of combination products.

The following list shows the active pharmaceuticals used singly or in combination in cough and cold medicines in Australia. For ease of reading, chemical names have been abbreviated where ambiguity is avoidable. The list is not necessarily a complete one. Some medicines contain paracetamol or ibuprofen as well, but such combinations are not listed below. Some may also contain demulcents and other additives.

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Codeine Codeine, pseudoephedrine Codeine, pseudoephedrine, ammonium chloride, guaifenesin Dextromethorphan Dextromethorphan, pseudoephedrine Dextromethorphan, pseudoephedrine, chlorpheniramine Dextromethorphan, pseudoephedrine, diphenhydramine hydrochloride Dextromethorphan, brompheniramine, phenylephrine Dihydrocodeine Pentoxyverine Pholcodine Pholcodine, chlorpheniramine, ammonium chloride, phenylephrine Pholcodine, chlorpheniramine, pseudoephedrine Pholcodine, bromhexine Pholcodine, pseudoephedrine Pholcodine, promethazine Ammonium chloride Ammonium chloride, diphenhydramine Bromhexine Bromhexine, guaifenesin Bromhexine, pseudoephedrine Bromhexine, pseudoephedrine, guaifenesin Guaifenesin Guaifenesin, pseudoephedrine Ipecacuanha Phenylephrine Phenylephrine, chlorpheniramine Phenylephrine, brompheniramine Pseudoephedrine Pseudoephedrine, chlorpheniramine A cough or cough and cold medicine, then, could be a sedating antihistamine, or an antitussive, or an expectorant or a decongestant, with a single active, or a combination, such as ? Antihistamine + antitussive Antihistamine + expectorant Antihistamine + decongestant Antihistamine + antitussive + decongestant

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Antihistamine + antitussive + expectorant + decongestant

Antitussive + expectorant

Antitussive + decongestant

Antitussive + two expectorants + decongestant

Two expectorants

Expectorant + decongestant

Two expectorants + decongestant

and in addition may contain an analgesic/antipyretic, a demulcent and/or other constituents. Clearly, then, the term `cough and cold medicines' does not refer to largely similar products, and evidence of efficacy and safety will not be available for many of the combinations listed above.

Label claims vary, even for similar products, not least as most were given approval long ago, prior to current approval mechanisms. We have not done a full review of stated indications on labels, but note that they follow similar patterns e.g. antitussives are often described as `cough suppressants for unproductive dry cough associated with colds and flu' and combination products as for `dry raspy cough and cold symptom relief'. Decongestants will often be described as such, as are expectorants, assuming that these terms are commonly understood by the lay public. The term `chesty cough' in product names is often associated with a mucolytic or an expectorant, i.e. suggesting a productive cough, but the latter is not always specified. The word `temporary' is increasingly used on labels preceding `relief'.

5. `Coughs and colds' ? what are we treating?

Cough and cold medicines in children are used for acute or recurrent cough, usually without a definite diagnosis, and for cough and other symptoms believed by a parent to be due to the common cold. The brief discussion to follow refers to causes of these symptoms and to symptom patterns associated with common respiratory illnesses in childhood. This is relevant to the question ? does it matter if parents have made the `wrong diagnosis', and if so is the use of cough and cold medicines a hazard to the child?

Allergy is a common cause of acute cough, often in association with acute allergic rhinitis. This combination of symptoms is often indistinguishable from a mild acute viral respiratory infection ? to the sufferer, to a parent, and to an experienced professional. The cough does not necessarily imply the presence of asthma, and presumably results from antigen stimulation of laryngeal, tracheal and other cough receptors.

Acute viral respiratory infection is the commonest cause of cough in childhood. Numerous other infections cause acute or recurrent cough, as do acute asthma, chemical irritation (cigarette smoke), airway foreign body, tumours, structural abnormalities and many rarer causes.

Most acute respiratory infections are self-limiting and require no specific treatment. Acute cough may also herald severe, even potentially life threatening infections, including those that may require specific therapy, such as bronchiolitis, croup, pneumonia, mediastinal obstruction, etc. Does the availability and use of OTC cough and cold medicines delay the diagnosis of these serious conditions and lead to poorer outcomes?

Acute respiratory infection: children suffer an average of 6-8 respiratory infections each year, mostly mild and requiring no treatment. Most of these infections are caused by viruses: rhinovirus, Respiratory syncytial virus, influenza and parainfluenza viruses, metapneumovirus, adenoviruses, some Coxsackie and echoviruses and many others. Most of these can produce some or all of the different patterns of respiratory illness seen in children:

? Coryza (common cold)

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? Viral pharyngitis

? Acute otitis media

? Acute sinusitis

? Acute laryngotracheitis (croup)

? Acute bronchiolitis

? Acute viral bronchitis

? Viral pneumonia

Coryza: Mild colds may last only 1-2 days and feature no more than sneezing, nasal obstruction and nasal discharge. Cough and sore throat are variable. More severe colds may be associated with fever, headache, muscle aches and pains, malaise and, in infants, feeding difficulty. Cough may sometimes persist for a few weeks. Nasal obstruction is an early symptom which usually subsides quickly. Colds are quite often followed by otitis media, less often by sinusitis. Most often this is directly due to viral infection, and not complicating bacterial infection. The cough is presumably a direct effect of the virus. With no more than cold symptoms, rhinovirus can be present from nose to smaller bronchi.

Viral pharyngitis: Viral pharyngitis and tonsillitis are seen in children of all ages; bacterial (usually streptococcal) tonsillitis is unusual in children aged less than 4 years. Fever, malaise and sore throat along with pharyngeal inflammation prompt the diagnosis but cough and coryza are often present as well. Cervical lymph nodes are often palpable. Constitutional symptoms vary from mild to severe. Many parents will know from experience that such illnesses are self limiting and appropriately not seek professional advice most of the time. Cough and cold medicines will often be used for such illnesses. Pharyngitis is part of infectious mononucleosis and many less common infections.

Otitis media, acute sinusitis and acute laryngotracheitis all produce symptoms which would suggest more than `coughs and colds'. The use of cough and cold medicines with prodromal symptoms would not influence the course of these illnesses.

Acute bronchiolitis (a viral infection largely affecting infants aged less than 12 months) and viral bronchitis are common illnesses which usually commence with a coryzal prodrome. Treating the cough associated with these infections, and also with viral pneumonia, is unlikely to have either beneficial or adverse effects, although this question does not appear to have been systematically examined. It is worth noting that antitussives have not been shown to be effective in pertussis, where paroxysmal cough can be life threatening in infants.

6. Who uses these medicines? What do they expect from them?

There is limited information about patterns of use of cough and cold medicines across the Australian community. What proportion of families use them often, infrequently or never? How much use is based on favourable experience, professional advice, lay advice, promotion, and/or hope of a good night's sleep for everyone? In a paper describing an Australian qualitative study,1 the authors point out that self-medication (of children, by parents) became a widespread phenomenon in western countries more than 100 years ago. They develop a convincing concept of `social medication' which in part is aimed at modifying child behaviour to more acceptable patterns, and in part a `coping strategy'. They found that paracetamol was the commonest `social medication', followed by cough and cold medicines or sedating antihistamines. They noted that parents may believe in benefits from drugs which go beyond conventional pharmacology. For instance, some parents incorrectly attribute paracetamol as having sedative or calming properties quite separate to any analgesic or antipyretic effect.

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